Benzene-sulphonamido derivatives and process of making same



Patented Aug. 14, 1945 e 1 'BENZENE-SULPHONAIVHDO DERIVATIVES AND PROCESS OF MAKING SAME Max Hartmann, Riehen, and Jean Druey, Basel,

I Switzerland, assignors to 'Ciba Pharmaceutical Products, Incorporated, Summit, N. J., a corporation of New Jersey No Drawing. Application April 23, 1941, Serial No. 390,012. In Switzerland June 1,1940

. 9 Claims.

This invention relates to the manufacture of new hydroxylamino derivativesof-the benzenesulphonamido-thiazole series by -causing a reducing agent toact on 9. nitroor nitroso-derivative of. the 1benzene-sulphonamido-thiazole series or bycausing. an oxidizing agent to act on an amino-derivative of an N-mono-substituted amino-derivativeof this series. v i

The reduction or oxidation may be conducted by methods known inorganic chemistry for the preparation of aryl-hydroxylamines (compare Richter-Anschiitz, Chemie der Kohlenstofiverbindungen, 12th edn., Vol. 2, pages 78-80 [1935], J Houben, ;Die Methoden" der organischen Chemie, 3rd edn., Vol. 2, pages 175-178 and pages 403-409 [1925])- For reduction ofithe nitroor nitroso-group there may advantageously be used zinc dust, amalgams such as a zinc ortaluminium amalgam, ammoniumor alkali-sulphides or sulph-hydrates, stannous chlorideand so on, in the presence of waterand/or an organic solvent such as alcohol, dioxane or the like. Electrolytic or catalytic methods of reduction may also be used. Reduction by means of hydrogen in presence of a catalyst of the platinum group such as palladium, or in the presence of nickel or cobalt or mixtures of catalysts and the like, has proved to be particularly advantageous. In this procedure it has beeniound. surprisingly, that after absorption of the quantity of hydrogen required for the formation of the hydroxylamino compound no further hydrogenis absorbed. The oxidation of aminor N-mono-substituted amino-benzene-sulphonamido thiazoles may be conducted by means oi inorganic and organic peracids and peroxideshfor example by means of mono-sulpho-peracid. l v a As parent materials for th invention there may be used for example, benzene-sulphonamidothiazoles which are substituted in the benzene nucleus, particularly in para-position, by a nitro-, nitroso-, amino-, alkylamino or acyl-- amino-group and may contain in the thiazole residue substituents such as ,alky1-, oxy-, alkoxy-, carboxyor carbalkoxy-groups.

The following compounds, for example, may be made in accordance with the invention: 2- [parahvdroxylaminobenzenesulphonamidol thiazole, 2 [para-hydroxylaminobenzenesulphonamidol- 4-methy1-thiazole, 2-[para-hydroxylaminobenzenesulphonamido] -4-ethyl-thiazole, 2 [parahydroxylaminobenzenesulphonamido] 4:5 dimethyl-thiazole, 2- [para-hydroxylaminobenzenesulphonamidol-4-methy1-4z5 dihydro-thiazole,

- ride with 2-aminothiazole, for example inpyridine.

The compounds obtainable in accordance with the invention form soluble salts with 'alkalis, alkaline earths and organic bases.

The products may be converted in manner itself known into various acyl-derivatives of organic or inorganic acids.

The new compounds are distinguished by a Par- I ticularly high activity in the case of illnesses resulting from infection The following examples illustrate the invention, the parts being by weight:

Eaampl e 1 14 grams of 2-[para-nitrobenzenesulphonamidol-thiazole (prepared by reaction of paranitrobenzene-sulphonic acid chloride with 2- amino-thiazole for example in pyridine) are dissolved in 700 cc. of alcohol of 96 per cent strength and at room temperature dryammonia gas and then hydrogen sulphide are introduced into the solution. The solution is then strongly cooled and ammonia and hydrogen sulphide are introduced until the solution is super-saturated with these gases. The reaction: mixture is then allowed to stand for some time in an ice chest and is then poured into cold water and acidified with acetic acid. After the whole has been allowed to stand for a day,the mixture of 2- [parahydroxylaminobenzenesulphonamidol thiazole and sulphur which has precipitated, is filtered. The solid matter is extracted with boiling water and filtered hot. From the filtrate 2-[para-hydroxylaminobenzenesulphonamido]-thiazo1e separates in the form of nearly white needles. A further quantity can be obtained by saturating the acetic acid mother liquor with common salt.

The same compound can also be obtained by cautious oxidation of 2-[para-amino-benzenesulphonamidol-thiazole with monosulphoperacid.

2 [para-hydroxylaminobenzenesulphonamidol- The 2-[para-hydroxylaminobenezensulphona- 'of white or yellowish needles.

I solutions.

midol-thiazole crystallizes from water in the form It is moderately soluble in water, methyl alcohol and ethyl alcohol at a raised temperature. It is dissolved easily by alkalis, alkaline earths, ammonia, alkali-carbonates, pyridine and-the like; tol formyellow It is also soluble in mineral acids which are not too dilute. It reduces silver nitrate solution, alkaline with ammonia, at a raised tem'-' perature, and when heated with benzaldehyde in alcoholic solution forms a condensation productf in the form of leaflets. When heated in a small melting point tube it becomes dark.from=170? .C.:

upwards and melts with decomposition .at240-250 1 C. If a sample in a small tube is introduced into a mass having a temperature of 210215 C. it melts with foaming and again solidifies.

By reaction of the 2-[para-hydroxylaminobenr' zenesulphonamido]-thiazole in aqueous solution sorption of hydrogen ceasesafter about 4 /2 hours,

The reactionv mixtureis filtered with suction and the residue is extracted with 2500 parts of boiling water and filtered at boiling temperature. On cooling the filtrate,- 2+[para-hydroxylaminobenzenesulphonamidol -th,iaz oler is obtained with a yield of 60-70 percent and. maybe obtained completely pure by one recrystallization from water. Afurther smalhquantityof the product can be obtained from the alcoholicwfiltrateby evaporation, and recrystallization from water.

- 2 [para-hydroxylaminobenzenesulphonamido] 4-methyl-thiazo1e, 2-[para-hydroxylaminobem zenesulphonamidol-4rethyl-thiazo1e; 2- [para-hydroxylaminobenzenesulphonamidol 4:5 di-, methyl-thiazole or 2- [para-hydroxylaminobenzenesulphonamidol -5-carbethozy-thiazole may be roduced; in similar manner; Instead of ,the nitro compound, 'the corresponding nitroso compound may be used as starting material. I

These compounds may 'be obtained also by. careful oxidation of the corresponding amino, compounds, for examplewith monosulphopeh;

acid. When .using N-mono-substituted compounds as starting materials, for. example 2- [para-methylaminobenzenesulphonamidol -thi-.

azole, 2 [para-benzylaminobenzenesulphonami do] -4-methyl-thia'zole or 2-[para-pyridylamino-. benzenesulphonamidol-4-ethylthiazole, the corresponding hydroxylamino compounds are ob.- tained therefrom by oxidation, for example 2- [para methylhydroxylaminobenzenesulphona-- midol-thiazole, 2 [para-benzylhydroxylamino-- benzenesulphonamido] -4-methyl-thiaz'ole on 2-- [para pyridylhydroxylaminobenzenesulphonamidol -4-ethyl-thiazole. The starting materials may be prepared by the action of the corresponding aldehydes on the amino compounds and subsequent reduction or by reaction of the corresponding halogenv hydrocarbons with the amino compounds. I

The cited hydroxylamine compounds may be converted into the corresponding acyl compounds by reaction with acid anhydrides or acid ch- I rides, for example with. acetic acid-, propionic acid-', capric acid-, benzoic acidor nicotinic acid-anhydride or -chloride.

Salts of 4 the above indicated compounds may be'obtained' by'jr'eacting these compounds with alkalis, alkaline earths or organic bases, for example with calcium hydroxide or aminoethanol,

.lor by doublefreaction of the corresponding salts. .In this manner for instance the calcium salt of 2 [para-hydroxylaminobenzenesulphonamidolthiazole or of 2-[parahydroxylaminobenzenesulphonamidol-4methyl-thiazole may be obtained.

What We claim is':" 11:;

,1. Process 'for the manufactureof 2'-[parahydroxylaminobenzenesulphonamidol-4-methylthiazole, comprising causing hydrogen to act on 2 lpara-nitrobenzenesulphonamido] -4--methyl'- thiazole in the presence. of a catalyst selected from the catalysts of'the platinum and' nickelgroups.

2. Process-for :.the manufacture 'of 2- [parahydroxylaminobenzenesulphonamido]- thiazole, comprising causing hydrogen to act on 2--[paranitro benzenesulphonamidol thiazole in the presence of a catalyst selected from the-catalysts of the platinum andnickel groups.

.3. Process for themanufacture-of 2-[parahydroxylaminobenzenesulphonamido] A-methylthiazole, comprising causing hydrogen to acton 2 [para-nitro benzenesulphonamido] 4- m'ethyl-thiazole in the presence of palladium 4. Processl for the manufacture of 2-[parahydroxylaminobenzenesulphonamidol thiazole, comprising causing hydrogen to act on 2-ipara-j.

nitro benzenesulphonamido]Qthiazole "in the presence of palladium.

5. The calcium salt of 2 -[para-hydroxylaminobenrzen'esulphoniamidol -4-methyl-thiaz'ole.

6; The calcium salt 'of- 2-[para-hydroxyl 4-methyl-thiazole which is freefrom othrsub-i stituents and the 2-(para-hydroxylaminobenzenesulphonamido) -thiaz'ole which is free from other substituents, and its calcium salt.

- 9. The calcium salt of 'a member of the group. consisting of the 2- (para-hydroxylaminoben'zenes'ulphonamido) -4-methyl-thiazole which is free' from other substituents" and the 2-'(para-hydroxylaminobenzenesulphonamido) 5th i a' z '0 1e which is free from other subsfiituentsg 

